The nitrate ester, glyceryl trinitrate (GTN) or nitroglycerin, has been used as a vasodilator in the treatment of angina pectoris for over a hundred years, and the dominant contemporary belief is that GTN exerts its therapeutic effect through in vivo release of nitric oxide (NO). Other organic nitrates, such as isosorbide dinitrate, have also been identified as effective and clinically important vasodilators. NO itself has been identified as Endothelium Derived Relaxing Factor (EDRF) and several classes of compounds, for example nitrosothiols, in addition to organic nitrates, have been proposed as NO donors or NO prodrugs. Well-known examples of these classes of compounds and GTN itself have been suggested to demonstrate neurotoxic or neuroprotective effects by dint of interactions with the redox modulatory site of the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor. Thus GTN is firstly a potent vasodilator and secondly possesses neuroprotective properties. Several attempts have been made to increase the efficacy or potency of alternative nitrate esters as vasodilators relative to GTN, for example, by incorporation of propanolamine or cysteine functionalities. However, no attempt has been made to separately regulate the vasodilatory and neuroprotective effects of GTN. Indeed, postural hypertension, weakness and other signs of cerebral ischemia are adverse effects, associated with the vasodilatory effects of GTN and observed in treatment, which are highly contraindicative of GTN itself as a clinically useful neuroprotective therapeutic agent.
In as much as the potent vasodilatory effects of nitrate esters may prove (a) deleterious to or alternatively (b) synergistic with the neuroprotective effects of GTN, it is postulated herein that regulation of these two effects is required for development of new and useful neuroprotective therapeutic agents. Further, it is postulated that such regulation may be achieved through use of nitrate esters incorporating sulfur-containing or phosphorus-containing functionalities into the structure of the nitrate esters or through use of their congeners. Interaction of nitrate esters with amino acid neurotransmitter receptors, including the NMDA receptor, will provide examples of compounds with neuroprotective properties, but modulation of the .gamma.-aminobutyric acid (GABA) receptor response will provide examples of nitrate esters capable of cognition enhancement. These postulates are based, in part, on bioassay data on such compounds. Thus, there is a need for synthetic aliphatic nitrate esters containing sulfur or phosphorus functionalities or their congeners as new and useful therapeutic agents for use in neuroprotection and/or cognition enhancement. It will be appreciated, therefore, that these compounds can be used for treatment of: stroke; Parkinson's disease; Alzheimer's disease; Huntington's disease; multiple sclerosis; amyotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever-induced seizures; trauma to the head; hypoglycemia; hypoxia; myocardial infarction; cerebral vascular occlusion; cerebral vascular hemorrhage; hemorrhage; environmental excitoxins of plant, animal and marine origin; dementias of all type, trauma, drug-induced brain damage, aging.